Abstract
Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. In this review, we focus on the cell proliferative functions and regulatory mechanisms of calcineurin and summarize the various substrates of calcineurin. We also describe recent advances regarding dysregulation of the calcineurin activity in cancer cells. We hope that this review will provide new insights into the potential role of calcineurin in cancer development.
Highlights
Intracellular calcium ions (Ca2+) act as pleiotropic secondary messengers in key signaling pathways involving a variety of cellular functions
Cell division is precisely regulated by a series of cyclin-dependent kinase (CDK), whose activity is dependent on the binding to different cell cycle-specific cyclins [15]
CaM-dependent protein kinases (CaMK) regulates cell cycle progression from G1 to S phase [42,43], and negatively regulates the expression of p27, which is an inhibitor of CDK4-cyclin D and CDK2-cyclin E [44]
Summary
Intracellular calcium ions (Ca2+) act as pleiotropic secondary messengers in key signaling pathways involving a variety of cellular functions. Pande et al (1996) measured the intracellular levels of free cytoplasmic Ca2+ in rat fibroblasts and found that complex changes occurred in calcium levels during the cell cycle [10]. They showed that the levels of Ca2+ were the lowest at the beginning of the G1 phase but were subsequently increased at the G1/S border. The molecular mechanisms through which Ca2+/CaM regulates cell cycle progression, especially through the activation state of the cyclin-dependent kinase (CDK) complex, is of great interest, and has been studied intensively. We discuss the latest findings of CaN in cell proliferation and its potential as a new therapeutic target in the treatment of cancer
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